The MEN1 gene is a likely tumor suppressor gene because tumors in multiple endocrine neoplasia type 1 (MEN1) show loss of heterozygosity (LOH) at this locus and because sporadic tumors of the same tissues also show 11q13 LOH implicating this gene through a similar mechanism. We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We find germline mutations in 90-95% of probands with familial MEN1 or with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have not shown MEN1 mutations. We will continue to explore these and other states for germline MEN1 mutations. We have also found somatic MEN1 mutation in 20% of parathyroid tumors not associated with MEN1. We will also determine the spectrum of pathologic states that MEN1 gene contributers to through mutation and other mechanisms. We have also initiated studies on the expression and actions of the encoded menin RNA and protein. The gene has been expressed in E. Coli and mammalian cells and will be overexpressed in insect cells. And vector constructs are being developed to express mutant forms. Its interactions with other proteins are being studied by immunoprecipitation and by the yeast 2-hybrid system. These studies should help identify its biochemical activities.